Submissions for variant NM_015443.4(KANSL1):c.611dup (p.Met205fs)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002790017	SCV003761370	pathogenic	Koolen-de Vries syndrome	2023-01-25	criteria provided, single submitter	curation	The heterozygous p.Met205TyrfsTer9 variant in KANSL1 was identified by our study in one individual with global developmental delay, agenesis of the corpus callosum, and ventricular septal defect. Trio exome analysis showed this variant to be de novo. This variant has been previously reported in one individual with Koolen de Vries syndrome, where it was found to be de novo (PMID: 26424144). This variant was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 205 and leads to a premature termination codon 9 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the KANSL1 gene is an established disease mechanism in Koolen de Vries syndrome. In summary, this variant meets criteria to be classified as pathogenic for Koolen de Vries syndrome. ACMG/AMP Criteria applied: PVS1, PS2_Moderate, PM2_Supporting (Richards 2015).
GeneDx	RCV003159244	SCV003853045	pathogenic	not provided	2023-03-27	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32565546, 26424144)
Fulgent Genetics, Fulgent Genetics	RCV002790017	SCV005644161	likely pathogenic	Koolen-de Vries syndrome	2024-06-19	criteria provided, single submitter	clinical testing
GenomeConnect - Brain Gene Registry	RCV002790017	SCV003931258	not provided	Koolen-de Vries syndrome		no assertion provided	phenotyping only	Variant classified as Pathogenic and reported on 02-18-2020 by GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.